Glucocorticoid resistance of allogeneic T cells alters the gene expression profile in the inflamed small intestine of mice suffering from acute graft-versus-host disease

被引:10
|
作者
Li, Hu [1 ]
Kaiser, Tina K. [1 ]
Borschiwer, Marina [2 ]
Bohnenberger, Hanibal [3 ]
Reichardt, Sybille D. [1 ]
Luehder, Fred [4 ]
Walter, Lutz [5 ]
Dressel, Ralf [1 ]
Meijsing, Sebastiaan H. [2 ]
Reichardt, Holger M. [1 ]
机构
[1] Univ Med Ctr Gottingen, Inst Cellular & Mol Immunol, Humboldtallee 34, D-37073 Gottingen, Germany
[2] Max Planck Inst Mol Genet, Ihnestr 63, D-14195 Berlin, Germany
[3] Univ Med Ctr Gottingen, Inst Pathol, Robert Koch Str 40, D-37075 Gottingen, Germany
[4] Univ Med Ctr Gottingen, Inst Neuroimmunol & Multiple Sclerosis Res, von Siebold Str 3a, D-37075 Gottingen, Germany
[5] Leibniz Inst Primate Res, Primate Genet Lab, German Primate Ctr, Kellnerweg 4, D-37077 Gottingen, Germany
关键词
Glucocorticoids; T cells; Gene expression; RNAseq; GvHD; MOLECULAR-MECHANISMS; HEME OXYGENASE-1; METABOLISM; RECEPTOR; DIFFERENTIATION; LYMPHOCYTES; ACTIVATION; INDUCTION; CAPACITY; TARGETS;
D O I
10.1016/j.jsbmb.2019.105485
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Glucocorticoids (GCs) play an important role in controlling acute graft-versus-host disease (aGvHD), a frequent complication of allogeneic hematopoietic stem cell transplantation. The anti-inflammatory activity of GCs is mainly ascribed to the modulation of T cells and macrophages, for which reason a genetically induced GC resistance of either of these cell types causes aggravated aGvHD. Since only a few genes are currently known that are differentially regulated under these conditions, we analyzed the expression of 54 candidate genes in the inflamed small intestine of mice suffering from aGvHD when either allogeneic T cells or host myeloid cells were GC resistant using a microfluidic dynamic array platform for high-throughput quantitative PCR. The majority of genes categorized as cytokines (e.g. Il2, Il6), chemokines (e.g. Ccl2, Cxcl1), cell surface receptors (e.g. Fas1, Cda4) and intracellular molecules (e.g. Dusp1, Arg1) were upregulated in mice transplanted with GC resistant allogeneic T cells. Moreover, the expression of several genes linked to energy metabolism (e.g. Glut1) was altered. Surprisingly, mice harboring GC resistant myeloid cells showed almost no changes in gene expression despite their fatal disease course after aGvHD induction. To identify additional genes in the inflamed small intestine that were affected by a GC resistance of allogeneic T cells, we performed an RNAseq analysis, which uncovered more than 500 differentially expressed transcripts (e.g. Cxcr6, Glut3, Otc, Aoc1, Il1r1, Sphk1) that were enriched for biological processes associated with inflammation and tissue disassembly. The changes in gene expression could be confirmed during full-blown disease but hardly any of them in the preclinical phase using high-throughput quantitative PCR. Further analysis of some of these genes revealed a highly selective expression pattern in T cells, intestinal epithelial cells and macrophages, which correlated with their regulation during disease progression. Collectively, we identified an altered gene expression profile caused by GC resistance of transplanted allogeneic T cells, which could help to define new targets for aGvHD therapy.
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页数:13
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